title: Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis.
abstract: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreting proteinase. To fully understand the function of MMP12 in myeloid lineage cells, a myeloid-specific c-fms-rtTA/(TetO)₇-CMV-MMP12 bitransgenic mouse model was created. In this bitransgenic system, induction of MMP12 abnormally elevated frequencies and numbers of common myeloid progenitor (CMP) and granulocyte/macrophage progenitor (GMP) populations, and decreased the frequency and number of the megakaryocyte/erythrocyte progenitor (MEP) population in the bone marrow (BM). The CD11b(+)/Gr-1(+) immature cell population was systemically increased in multiple organs. Both in vitro and in vivo studies showed an immunosuppressive function on T-cell proliferation and function by CD11b(+)/Gr-1(+) immature cells from MMP12-overexpressing bitransgenic mice. MMP12 directly stimulated lineage-negative (Lin⁻) progenitor cells to differentiate into CD11b(+)/Gr-1(+) immature cells that showed immunosuppression on T-cell proliferation and function in vitro. Regulatory T cells (Tregs) were increased. In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression. BM chimeras confirmed that the MMP12-induced myeloid cell autonomous defect led to abnormal myelopoiesis, immune suppression, and lung adenocarcinoma.
authors.affiliation: The Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Qu
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
authors.forename: Hong
authors.initials: H
authors.lastname: Du
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D011650:Pulmonary Alveoli / Q000166:cytology; D011956:Receptors, Cell Surface / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D011956:Receptors, Cell Surface; C551746:granulocyte receptor 1, mouse; D053508:Matrix Metalloproteinase 12